NLRX1 is a regulator of mitochondrial antiviral immunity

The RIG- like helicase ( RLH) family of intracellular receptors detect viral nucleic acid and signal through the mitochondrial antiviral signalling adaptor MAVS ( also known as Cardif, VISA and IPS- 1) during a viral infection(1-6). MAVS activation leads to the rapid production of antiviral cytokines, including type 1 interferons. Although MAVS is vital to antiviral immunity, its regulation from within the mitochondria remains unknown. Here we describe human NLRX1, a highly conserved nucleotide- binding domain ( NBD)- and leucine- rich- repeat ( LRR)- containing family member ( known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS- mediated interferon-beta promoter activity and in the disruption of virus- induced RLH-MAVS interactions. Depletion of NLRX1 with small interference RNA promotes virus- induced type I interferon production and decreases viral replication. This work identifies NLRX1 as a check against mitochondrial antiviral responses and represents an intersection of three ancient cellular processes: NLR signalling, intracellular virus detection and the use of mitochondria as a platform for anti- pathogen signalling. This represents a conceptual advance, in that NLRX1 is a modulator of pathogen- associated molecular pattern receptors rather than a receptor, and identifies a key therapeutic target for enhancing antiviral responses.